Closed loop control with improved alarm functions

ABSTRACT

Methods, system and devices for monitoring control parameters in a closed loop control operation including continuously monitoring glucose level and automatic administration of a medication, detecting a condition associated with hypoglycemia, determining whether a probability of the detected condition associated with hypoglycemia exceeding a threshold level, and outputting a notification based upon the determination are provided.

RELATED APPLICATION

The present application is a continuation of U.S. patent applicationSer. No. 12/202,305 filed Aug. 31, 2008, entitled “Closed Loop ControlWith Improved Alarm Functions”, the disclosure of which is incorporatedherein by reference for all purposes.

BACKGROUND

Benefits of a closed loop control system for treating diabeticconditions with monitoring glucose levels and adjusting delivery rate ofinsulin are well known. Such systems, referred to as artificialpancreas, model healthy pancreas which, when functioning normally,produces insulin (by the beta cells (β-cells)) to counteract the rise inglucose levels in the blood stream. As is known, Type-1 diabetesmellitus condition exists when the beta cells in the pancreas either dieor are unable to produce sufficient amount of insulin naturally inresponse to the elevated glucose levels.

Common treatment of Type-1 diabetes is the use of insulin pumps that areprogrammed to continuously deliver insulin to the body through aninfusion set. The use of insulin pumps to treat Type-2 diabetes (wherethe beta cells in the pancreas do produce insulin, but an inadequatequantity) is also becoming more prevalent. Such insulin delivery devicesare preprogrammed with delivery rates such as basal profiles which aretailored to each user, and configured to provide the needed insulin tothe user. Additionally, the preprogrammed delivery rates may besupplemented with periodic administration of bolus dosages of insulin(for example, correction bolus or carbohydrate bolus) as may be neededby the user.

In addition, continuous glucose monitoring systems have been developedto allow real time monitoring of fluctuation in glucose levels. Oneexample is the FreeStyle Navigator® Continuous Glucose Monitoring Systemavailable from Abbott Diabetes Care Inc., of Alameda, Calif. The use ofsuch glucose monitoring systems provides the user with real time glucoselevel information. Using the continuous glucose monitoring system, forexample, diabetics are able to determine when insulin is needed to lowerglucose levels or when additional glucose is needed to raise the levelof glucose.

With the continued rise in the number of diagnosed diabetic conditions,there is on-going research to develop closed loop control systems toautomate the insulin delivery based on the real time monitoring of thefluctuation in the glucose levels. Closed loop control algorithms suchas, for example, proportional, plus integral, plus derivative (PID)control algorithm or model predictive control algorithm exist and areused to control the automatic delivery of insulin based on the glucoselevels monitored. One key concern in such automated systems is safety.For example, the glucose sensor in the closed loop control system mayenter failure mode (permanently or temporarily) in which case themonitored glucose level in the closed loop control system will introduceerror and potentially result in undesirable or dangerous amounts ofinsulin being administered. Additionally, the infusion component in theclosed loop control system may have errors or experience failure modesthat results in an inaccurate amount of insulin delivered to the user.

Indeed, safety considerations as well as accuracy considerations toaddress and/or minimize the potential unreliability in the components ofthe closed loop control system are important to provide a robust controlsystem in the treatment of diabetic conditions.

SUMMARY

In one aspect, there are provided a method and device for monitoringcontrol parameters in a closed loop control operation includingcontinuously monitoring glucose level and automatic administration of amedication, detecting a condition associated with hypoglycemia,determining whether a probability of the detected condition associatedwith hypoglycemia exceeding a threshold level, and outputting anotification based upon the determination.

Also provided are systems and kits.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram illustrating an overall closed loop controlsystem in accordance with one embodiment of the present disclosure;

FIG. 2 is a flowchart illustrating adverse condition monitoring andcontrol in a closed loop control system in accordance with oneembodiment of the present disclosure;

FIG. 3 is a flowchart illustrating adverse condition monitoring andcontrol in a closed loop control system in accordance with anotherembodiment of the present disclosure;

FIG. 4 is a flowchart illustrating condition deviation monitoring andcontrol in a closed loop control system in accordance with oneembodiment of the present disclosure;

FIG. 5 is a flowchart illustrating analyte sensor condition monitoringand control in a closed loop control system in accordance with oneembodiment of the present disclosure;

FIG. 6 is a flowchart illustrating analyte sensor condition monitoringand control in a closed loop control system in accordance with anotherembodiment of the present disclosure;

FIG. 7 is a flowchart illustrating variable rate control in a closedloop control system in accordance with one embodiment of the presentdisclosure;

FIG. 8 is a flowchart illustrating variable rate control in a closedloop control system in accordance with another embodiment of the presentdisclosure;

FIGS. 9-10 are flowcharts illustrating blood glucose measurement toimprove accuracy of the closed loop control system in accordance withanother embodiment of the present disclosure;

FIG. 11 is a flowchart illustrating medication delivery information todetermine analyte sensor condition in a closed loop control system inaccordance with one embodiment of the present disclosure; and

FIG. 12 is a flowchart illustrating detection of false hypoglycemicalarm condition in a closed loop control system in accordance with oneembodiment of the present disclosure.

DETAILED DESCRIPTION

Before embodiments of the present disclosure are described, it is to beunderstood that this disclosure is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present disclosure will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present disclosure isnot entitled to antedate such publication by virtue of prior disclosure.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

Generally, embodiments of the present disclosure relate to methods andsystem for a robust closed loop control system with safety parametersfor continuously monitoring at least one analyte such as glucose in bodyfluid and delivering suitable levels of medication such as insulin. Incertain embodiments, the present disclosure relates to the continuousand/or automatic in vivo monitoring of the level of an analyte using ananalyte sensor, and under the control of a closed loop controlalgorithm, determining and delivering an appropriate level of medicationsuch as insulin in response to the monitored analyte level.

Embodiments include medication delivery devices such as externalinfusion pumps, implantable infusion pumps, on-body patch pumps, or anyother processor controlled medication delivery devices that are incommunication with one or more control units which also control theoperation of the analyte monitoring devices. The medication deliverydevices may include one or more reservoirs or containers to hold themedication for delivery in fluid connection with an infusion set, forexample, including an infusion tubing and/or cannula. The cannula may bepositioned so that the medication is delivered to the user or patient ata desired location, such as, for example, in the subcutaneous tissueunder the skin layer of the user.

Embodiments include analyte monitoring devices and systems that includean analyte sensor—at least a portion of which is positionable beneaththe skin of the user—for the in vivo detection, of an analyte, such asglucose, lactate, and the like, in a body fluid. Embodiments includewholly implantable analyte sensors and analyte sensors in which only aportion of the sensor is positioned under the skin and a portion of thesensor resides above the skin, e.g., for contact to a transmitter,receiver, transceiver, processor, etc.

A sensor (and/or a sensor insertion apparatus) may be, for example,configured to be positionable in a patient for the continuous orperiodic monitoring of a level of an analyte in a patient's dermalfluid. For the purposes of this description, continuous monitoring andperiodic monitoring will be used interchangeably, unless notedotherwise.

The analyte level may be correlated and/or converted to analyte levelsin blood or other fluids. In certain embodiments, an analyte sensor maybe configured to be positioned in contact with dermal fluid to detectthe level of glucose, which detected glucose may be used to infer theglucose level in the patient's bloodstream. For example, analyte sensorsmay be insertable through the skin layer and into the dermal layer underthe skin surface at a depth of approximately 3 mm under the skin surfaceand containing dermal fluid. Embodiments of the analyte sensors of thesubject disclosure may be configured for monitoring the level of theanalyte over a time period which may range from minutes, hours, days,weeks, months, or longer.

Of interest are analyte sensors, such as glucose sensors, that arecapable of in vivo detection of an analyte for about one hour or more,e.g., about a few hours or more, e.g., about a few days or more, e.g.,about three days or more, e.g., about five days or more, e.g., aboutseven days or more, e.g., about several weeks or at least one month.Future analyte levels may be predicted based on information obtained,e.g., the current analyte level at time, the rate of change of theanalyte, etc. Predictive alarms may notify the control unit (and/or theuser) of predicted analyte levels that may be of concern in advance ofthe analyte level reaching the future level. This enables the controlunit to determine a priori a suitable corrective action and implementsuch corrective action.

FIG. 1 is a block diagram illustrating an overall closed loop controlsystem in accordance with one embodiment of the present disclosure.Referring to FIG. 1, in one aspect, the closed loop control system 100includes an insulin delivery unit 120 that is connected to a body 110 ofa user or patient to establish a fluid path to deliver medication suchas insulin. In one aspect, the insulin delivery unit 120 may include aninfusion tubing fluidly connecting the reservoir of the delivery unit120 to the body 110 using a cannula with a portion thereof positioned inthe subcutaneous tissue of the body 110.

Referring to FIG. 1, the system 100 also includes an analyte monitoringdevice 130 that is configured to monitor the analyte level in the body110. As shown in FIG. 1, a control unit 140 is provided to control theoperation of the insulin delivery unit 120 and the analyte monitoringunit 130. In one embodiment, the control unit 140 may be a processorbased control unit having provided therein one or more closed loopcontrol algorithm to control the operation of the analyte monitoringdevice 130 and the delivery unit 120. In one aspect, the control unit140, the analyte monitoring unit 130 and the delivery unit 120 may beintegrated in a single housing. In other embodiments, the control unit140 may be provided in the housing of the delivery unit 120 andconfigured for communication (wireless or wired) with the analytemonitoring unit 130. In an alternate embodiment, the control unit may beintegrated in the housing of the analyte monitoring unit 130 andconfigured for communication (wireless or wired) with the delivery unit120. In yet another embodiment, the control unit 140 may be a separatecomponent of the overall system 100 and configured for communication(wireless or wired) with both the delivery unit 120 and the analytemonitoring unit 130.

Referring back to FIG. 1, the analyte monitoring unit 130 may include ananalyte sensor that is transcutaneously positioned through a skin layerof the body 110, and in signal communication with a compact datatransmitter provided on the skin layer of the body 110 which isconfigured to transmit the monitored analyte level substantially in realtime to the analyte monitoring unit 130 for processing and/or display.In another aspect, the analyte sensor may be wholly implantable in thebody 110 with a data transmitter and configured to wirelessly transmitthe monitored analyte level to the analyte monitoring unit 130.

Referring still to FIG. 1, also shown in the overall system 100 is adata processing device 150 in signal communication with the one or moreof the control unit 140, delivery unit 120 and the analyte monitoringunit 130. In one aspect, the data processing device 150 may include anoptional or supplemental device in the closed loop control system toprovide user input/output functions, data storage and processing.Examples of the data processing device 150 include, but not limited tomobile telephones, personal digital assistants (PDAs), in vitro bloodglucose meters, Blackberry® devices, iPhones, Palm® devices, data pagingdevices, and the like each of which include an output unit such as oneor more of a display, audible and/or vibratory output, and/or an inputunit such as a keypad, keyboard, input buttons and the like, and whichare configured for communication (wired or wireless) to receive and/ortransmit data, and further, which include memory devices such as randomaccess memory, read only memory, volatile and/or non-volatile memorythat store data.

Also shown in the overall system 100 is a data processing terminal 160which may include a personal computer, a server terminal, a laptopcomputer a handheld computing device, or other similar computing devicesthat are configured to data communication (over the internet, local areanetwork (LAN), cellular network and the like) with the one or more ofthe control unit 140, the delivery unit 120, the analyte monitoring unit130, or the data processing device 150, to process, analyze, store,archive, and update information.

It is to be understood that the analyte monitoring device 130 of FIG. 1may be configured to monitor a variety of analytes at the same time orat different times. Analytes that may be monitored include, but are notlimited to, acetyl choline, amylase, bilirubin, cholesterol, chorionicgonadotropin, creatine kinase (e.g., CK-MB), creatine, DNA,fructosamine, glucose, glutamine, growth hormones, hormones, ketones,lactate, peroxide, prostate-specific antigen, prothrombin, RNA, thyroidstimulating hormone, and troponin. The concentration of drugs, such as,for example, antibiotics (e.g., gentamicin, vancomycin, and the like),digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may alsobe monitored. In those embodiments that monitor more than one analyte,the analytes may be monitored at the same or different times.

Additional detailed descriptions of embodiments of the continuousanalyte monitoring device and system, calibrations protocols,embodiments of its various components are provided in U.S. Pat. Nos.6,175,752; 6,284,478; 7,299,082; U.S. patent application Ser. No.10/745,878 filed Dec. 26, 2003, issued as U.S. Pat. No. 7,811,231 onSep. 23, 2004, entitled “Continuous Glucose Monitoring System andMethods of Use”, each incorporated by reference in its entirety for allpurposes. Additional detailed description of systems includingmedication delivery units and analyte monitoring devices, embodiments ofthe various components are provided in U.S. patent application Ser. No.11/386,915, entitled “Method and System for Providing IntegratedMedication Infusion and Analyte Monitoring System”, the disclosure ofwhich is incorporated by reference for all purposes. Moreover,additional detailed description of medication delivery devices and itscomponents are provided in U.S. Pat. No. 6,916,159, the disclosure ofwhich is incorporated by reference for all purposes.

Referring back to FIG. 1, each of the components shown in the system 100may be configured to be uniquely identified by one or more of the othercomponents in the system so that communication conflict may be readilyresolved between the various components, for example, by exchanging orpre-storing and/or verifying unique device identifiers as part ofcommunication between the devices, by using periodic keep alive signals,or configuration of one or more devices or units in the overall systemas a master-slave arrangement with periodic bi-directional communicationto confirm integrity of signal communication therebetween.

Further, data communication may be encrypted or encoded (andsubsequently decoded by the device or unit receiving the data), ortransmitted using public-private keys, to ensure integrity of dataexchange. Also, error detection and/or correction using, for example,cyclic redundancy check (CRC) or techniques may be used to detect and/orcorrect for errors in signals received and/or transmitted between thedevices or units in the system 100. In certain aspects, datacommunication may be responsive to a command or data request receivedfrom another device in the system 100, while some aspects of the overallsystem 100 may be configured to periodically transmit data withoutprompting (such as the data transmitter, for example, in the analytemonitoring unit 130 periodically transmitting analyte related signals).

In certain embodiments, the communication between the devices or unitsin the system 100 may include one or more of an RF communicationprotocol, an infrared communication protocol, a Bluetooth® enabledcommunication protocol, an 802.11x wireless communication protocol,internet connection over a data network or an equivalent wirelesscommunication protocol which would allow secure, wireless communicationof several units (for example, per HIPAA requirements) while avoidingpotential data collision and interference.

In certain embodiments, data processing device 150, analyte monitoringunit 130 and/or delivery unit 120 may include blood glucose meterfunctions or capability to receive blood glucose measurements. Forexample, the housing of these devices may include a strip port toreceive a blood glucose test strip with blood sample to determine theblood glucose level. Alternatively, a user input device such as an inputbutton or keypad may be provided to manually enter such information.Still further, upon completion of a blood glucose measurement, theresult may be wirelessly and/or automatically transmitted to anotherdevice in the system 100. For example, it is desirable to maintain acertain level of water tight seal on the housing of the delivery unit120 during continuous use by the patient or user. In such case,incorporating a strip port to receive a blood glucose test strip may beundesirable. As such, the blood glucose meter function including thestrip port may be integrated in the housing of another one of thedevices or units in the system (such as in the analyte monitoring unit103 and/or data processing device 150). In this case, the result fromthe blood glucose test, upon completion may be wirelessly transmitted tothe delivery unit 120 for storage and further processing.

Any suitable test strip may be employed, e.g., test strips that onlyrequire a very small amount (e.g., one microliter or less, e.g., 0.5microliter or less, e.g., 0.1 microliter or less) of applied sample tothe strip in order to obtain accurate glucose information, e.g.FreeStyle® or Precision® blood glucose test strips from Abbott DiabetesCare Inc. Glucose information obtained by the in vitro glucose testingdevice may be used for a variety of purposes, computations, etc. Forexample, the information may be used to calibrate the analyte sensor,confirm results of the sensor to increase the confidence in the accuracylevel thereof (e.g., in instances in which information obtained bysensor is employed in therapy related decisions), determine suitableamounts of bolus dosage for administration by the delivery unit 120.

In certain embodiments, a sensor may be calibrated using only one sampleof body fluid per calibration event. For example, a user need only lancea body part one time to obtain sample for a calibration event (e.g., fora test strip), or may lance more than one time within a short period oftime if an insufficient volume of sample is obtained firstly.Embodiments include obtaining and using multiple samples of body fluidfor a given calibration event, where glucose values of each sample aresubstantially similar. Data obtained from a given calibration event maybe used independently to calibrate or combined with data obtained fromprevious calibration events, e.g., averaged including weighted averaged,etc., to calibrate.

One or more devices or components of the system 100 may include an alarmsystem that, e.g., based on information from control unit 140, warns thepatient of a potentially detrimental condition of the analyte. Forexample, if glucose is the analyte, an alarm system may warn a user ofconditions such as hypoglycemia and/or hyperglycemia and/or impendinghypoglycemia, and/or impending hyperglycemia. An alarm system may betriggered when analyte levels reach or exceed a threshold value. Analarm system may also, or alternatively, be activated when the rate ofchange or acceleration of the rate of change in analyte level increasesor decreases, reaches or exceeds a threshold rate of change oracceleration. For example, in the case of the glucose monitoring unit130, an alarm system may be activated if the rate of change in glucoseconcentration exceeds a threshold value which might indicate that ahyperglycemic or hypoglycemic condition is likely to occur. In the caseof the delivery unit 120, alarms may be associated with occlusionconditions, low reservoir conditions, malfunction or anomaly in thefluid delivery and the like. System alarms may also notify a user ofsystem information such as battery condition, calibration, sensordislodgment, sensor malfunction, etc. Alarms may be, for example,auditory and/or visual. Other sensory-stimulating alarm systems may beused including alarm systems which heat, cool, vibrate, or produce amild electrical shock when activated.

Referring yet again to FIG. 1, the control unit 140 of the closed loopcontrol system 100 may include one or more processors such asmicroprocessors and/or application specific integrated circuits (ASIC),volatile and/or non-volatile memory devices, and additional componentsthat are configured to store and execute one or more closed loop controlalgorithms to dynamically control the operation of the delivery unit 120and the analyte monitoring unit 130. The one or more closed loop controlalgorithms may be stored as a set of instructions in the one or morememory devices and executed by the one or more processors to vary theinsulin delivery level based on, for example, glucose level informationreceived from the analyte sensor.

As discussed in further detail below, the one or more control algorithmsof the control unit 140 are configured to monitor parameters andconditions associated with a safety indication of the closed loopcontrol system 100 and generate and notify the user, as may be desirableto perform one or more troubleshooting actions and/or automaticallyrevert to a semi-closed loop control mode or a manual control mode thatrequire some level of user, patient or healthcare provider intervention.

FIG. 2 is a flowchart illustrating adverse condition monitoring andcontrol in a closed loop control system in accordance with oneembodiment of the present disclosure. Referring to FIGS. 1 and 2, in oneembodiment, control unit 140 executing the closed loop system control isconfigured to monitor the closed loop control operation parameters(210). In one aspect, the closed loop control operation parameters maybe associated with the operation of the delivery unit 120, andoperational conditions associated therewith such as fluid delivery,amount of insulin delivered, potential occlusion and the like. Inaddition, the closed loop control operation parameters monitored mayalso include operational conditions associated with the analytemonitoring unit 130 such as, for example, the validity or integrity ofanalyte sensor signals, unanticipated sensor signal drop out, missingsensor data, and the like. Further, in embodiments where the deliveryunit 120 and analyte monitoring unit 130 are separate components in thesystem 100 communicating via wireless connection, monitored controloperation parameters may include the integrity of the communicationconnection between the devices or units in the system 100.

Referring to FIG. 2, when based on the monitored closed loop operationparameters an adverse condition associated with a safety state of theclosed loop operation is detected (220), it is determined whether thedetected adverse condition exceeds a preset safety level (230). Forexample, in the case where the adverse condition is associated with theintegrity of analyte sensor signals, it is determined whethersufficiently accurate glucose level can be derived based on the receivedsensor signals (for example, based on extrapolation using previouslyreceived sensor data, and/or in conjunction with a rate of change ofglucose level determination). The adverse condition detected may alsoinclude a determined medication delivery level that exceeds a presetthreshold level (for example, a physician determined maximum basaldelivery rate for the user). As a further example, the adverse conditiondetected may include communication failure between the components of theoverall system 100 including, the analyte monitoring unit 130 and thedelivery unit 120.

Referring back to FIG. 2, when it is determined that the detectedadverse condition does not exceed a preset safety level, in one aspect,the control unit 140 is configured to proceed with the execution of theclosed loop control algorithm based on the real time glucose datareceived from the analyte monitoring unit 130 to adjust the insulindelivery rate from the delivery unit 120, and the routine returns tomonitoring the closed loop operation parameters. On the other hand, ifit is determined that the detected adverse condition exceeds the presetsafety level, the control unit 140 in one embodiment is configured tocommand or instruct the delivery unit 120 to revert to a non-zeropre-programmed closed loop operation state within the safety level(240). For example, when it is determined that the determined insulinlevel for delivery exceeds the safety level or maximum delivery rate(for example, established by a physician or healthcare provider, or theuser, and programmed and stored in the control unit 140), the controlunit 140 is configured to automatically revert to an insulin deliveryrate that is within the safety level so that potential over-dosing maybe avoided.

In another aspect, the control unit 140 may be configured to issue acommand to the delivery unit 120 every 15 minutes (or some otherpredetermined time interval) which sets insulin delivery rate for a 20minute time period (or some other suitable time period). In the eventthat the adverse condition exceeding the preset safety level is detectedpreventing the control unit 140 to issue a new command to the deliveryunit 120 during the 20 minute time period, the control unit 140 isconfigured to instruct the delivery unit 120 to revert to apre-programmed delivery rate that is within the safety level (forexample, a less amount of insulin to be delivered). In a further aspect,the detected adverse condition may include a determination of insulin onboard value that, in conjunction with the insulin amount to bedelivered, exceeds the upper safety level of insulin delivery, thecontrol unit 140 may be configured to revert to or switch to a preset orpre-programmed level that would bring the insulin delivery amount to bewithin the determined safety level.

As discussed, in one aspect, the insulin delivery amount that is withinthe safety level may be pre-programmed in the control unit 140, forexample, and implemented as part of the closed loop control toautomatically deliver the insulin amount based on the pre-programmedlevel. In a further aspect, the control unit 140 may be configured tomodify or adjust the existing insulin delivery rate that is within thesafety level in response to the detected adverse condition, (forexample, reducing the determined insulin delivery rate by a certainfactor such as 75%, to maintain the insulin delivery amount within thesafety level).

In this manner, in one aspect, when adverse conditions associated withthe safety state of the closed loop control operation, the control unit140 may be configured to operate within a predefined safety range ratherthan requesting user intervention or disabling the closed loop controloperation to revert to a manual control operation mode. While certainexamples of adverse conditions are discussed above, within the scope ofthe present disclosure, any other condition associated with the safetylevel in the operation of the closed loop control system 100 arecontemplated, the detection of any of which initiates the evaluation ofthe detected condition and appropriate modification to the closed loopcontrol system parameters to continue operation of the closed loopcontrol operation without prematurely disabling the system, whilemaintaining the desired level of safety in using the closed loop controlsystem 100.

FIG. 3 is a flowchart illustrating adverse condition monitoring andcontrol in a closed loop control system in accordance with anotherembodiment of the present disclosure. Referring to FIGS. 1 and 3, in oneembodiment, control unit 140 (FIG. 1) retrieves a preset safety levelinformation (310) and compares the retrieved preset safety levelinformation to one or more detected adverse condition (320). Thereafter,a level of severity associated with the detected adverse condition isdetermined based, at least in part on the retrieved preset safety levelinformation (330). After determining the severity level, the controlunit 140 is configured to generate one or more closed loop operationinstructions based on the determined severity level for execution (340).

That is, in one aspect, when an adverse condition is detected by thecontrol unit 140, the control unit 140 (FIG. 1) is configured in oneaspect to determine how severe is the detected adverse condition withrespect to the automated insulin delivery. For example, control unit 140may detect a communication failure from the transmitter of the analytemonitoring unit 130 and thus not receive a current sensor dataindicative of the glucose level. However, the control unit 140 may havestored in one or more of its memory units previously received glucoselevels from the transmitter of the analyte monitoring unit 130. Given aninsulin delivery rate that is within the safety level, and a relativelystable glucose value (for example, based on a rate of change of glucosedetermination from previously received glucose data), the control unit140 may be configured to declare the communication failure as anon-critical adverse condition detected. In this manner, the generatedclosed loop operation instruction (340) may not modify the currentdelivery rate by the delivery unit 120 (FIG. 1).

On the other hand, if the rate of change of the glucose level indicatedby previously received sensor data demonstrates a rapid variation in theglucose level, and/or the communication failure persists over a timeperiod that exceeds a certain level (for example, exceeding 20 minutesor some other suitable time frame), the generated closed loop operationinstruction (340) may include commands to the delivery unit 120 (FIG. 1)to modify the delivery rate and/or revert to a pre-programmed deliveryrate that is within the previously determined safety level. In oneaspect, the control unit 140 (FIG. 1) may be configured to continuouslymonitor the presence of the detected adverse condition until thecondition is corrected, in which case, the generated closed loopoperation instruction (340) may include commands to the delivery unit120 to return to the prior closed loop control operation.

FIG. 4 is a flowchart illustrating condition deviation monitoring andcontrol in a closed loop control system in accordance with oneembodiment of the present disclosure. Referring to FIGS. 1 and 4, inanother aspect, control unit 140 (FIG. 1) monitors the closed loopoperation parameters (410) and when it detects one or more monitoredclosed loop operation parameters deviating from a predetermined level(420), the control unit 140 (FIG. 1) may be configured to generate andoutput a request for confirmation of the detected deviation of themonitored closed loop operation parameter (430).

For example, in the closed loop control system 100 (FIG. 1), a userinterface such as a display unit or audible/vibratory notification inthe insulin delivery unit 120 and/or the analyte monitoring unit 130 mayindicate a notification for the user to confirm the presence of thedetected deviation of the monitored closed loop operation parameter.Referring to FIG. 4, if the detected deviation of the monitored closedloop operation parameter is confirmed (440), in one aspect, the controlunit 140 (FIG. 1) may be configured to modify the closed loop controloperation based on the detected deviation of one or more of itsparameters (450). On the other hand, if the presence of the detecteddeviation of the monitored closed loop operation parameter is notconfirmed, then the control unit 140 (FIG. 1) may be configured todisable the closed loop control operation, and initiate a manualoperation mode (460) to deliver insulin by the delivery unit 120 (FIG.1).

In this manner, in one aspect, the control unit 140 (FIG. 1) may beconfigured to request for user confirmation or verification of thepresence of the detected adverse condition prior to initiatingresponsive corrective action, and further, when no verification orconfirmation is received, for example, within a set time period, thecontrol unit 140 (FIG. 1) may be configured to disable the closed loopcontrol operation. Accordingly, certain adverse conditions detected mayprompt the control unit 140 (FIG. 1) to request confirmation prior toautomatically responding to such occurrence of adverse condition, andfurther, when no confirmation is received, the control unit 140 (FIG. 1)may temporarily revert to a semi-closed loop or non-closed loop manualdelivery mode. In this manner, in certain aspects, a level of safety inusing the closed loop control system 100 is maintained, and dependingupon the particular detected adverse condition, the control unit 140 mayautomatically, temporarily adjust the delivery mode of the delivery unit120 (FIG. 1), or alternatively, require user intervention.

Furthermore, within the scope of the present disclosure, while thedetected conditions are described as adverse conditions, any parameteror condition associated with the operation of the closed loop controlsystem 100 are contemplated including, but not limited to, analytesensor operation, sensor signal filtering, sensor signal level, sensorcalibration, sensor signal attenuation, communication failure, signaloutlier condition, rate of change of the glucose level, insulin deliveryrate, insulin on board information, type of insulin, duration of theclosed loop control operation, number or frequency of bolus dosageadministration, predicted or projected glucose level and/or thedirection of the predicted or projected glucose level, frequency ofblood glucose measurements, maximum or minimum insulin delivery level,for example.

FIG. 5 is a flowchart illustrating analyte sensor condition monitoringand control in a closed loop control system in accordance with oneembodiment of the present disclosure. Referring to FIGS. 1 and 5, in oneembodiment, control unit 140 (FIG. 1) is configured to monitor closedloop operation parameters (510) in the closed loop control system 100(FIG. 1). When a potential fault or failure mode associated with theoperation of the analyte sensor is detected (520), the control unit 140is configured to retrieve and execute a preprogrammed delivery rate(530) (for example, a predetermined basal profile), while maintainingthe closed loop control operation mode. Further, the control unit 140 isconfigured to generate and output instructions or request to confirmand/or correct the detected potential fault or failure mode of theanalyte sensor (540).

That is, in one aspect, the closed loop control operation is notdisabled when it is initially detected that the analyte sensor may notbe properly functioning. Rather, the closed loop control operationincludes the execution of a pre-programmed delivery rate that isdetermined to be within a safety level, and when the potential faultcondition or failure mode has been corrected, the control unit 140 maybe configured to terminate the execution of the pre-programmed deliveryrate and resume real time automatic adjustment to the insulin deliveryrate based on the analyte sensor signals.

In this manner, rather than prematurely terminating the operation of theclosed loop control system 100 at a first indication of potentialfailure or fault of the analyte sensor, in one aspect, the control unit140 is configured to instruct the delivery unit 120 to execute apredetermined delivery rate that is within the safety level untilcorrective action related to the analyte sensor (for example, replacingthe sensor, or recalibrating the sensor with a blood glucosemeasurement) is performed. In a further aspect, the control unit 140 maybe configured to modify the retrieved predetermined delivery rate basedon the insulin delivered (for example, to consider the insulin on boardlevel) so that the safety level associated with the amount of insulin tobe delivered is maintained.

FIG. 6 is a flowchart illustrating analyte sensor condition monitoringand control in a closed loop control system in accordance with anotherembodiment of the present disclosure. Referring to FIGS. 1 and 6, inanother aspect, when the control unit 140 receives analyte sensoroperation information (610), one or more routines are performed toconfirm the proper operation of the analyte sensor (620). For example,the control unit 140 may be configured to verify the calibrationinformation of the analyte sensor so that the value level derivedtherefrom accurately indicates the monitored glucose level.

In a further aspect, the control unit 140 may be configured to retrievethe most recent sensor sensitivity determination based, for example, onthe reference blood glucose measurement received, and to compare theretrieved sensitivity to a stored nominal sensitivity for the sensor toconfirm a variation between sensitivities not exceeding a predeterminedlevel. In another aspect, when a scheduled calibration event occurs tocalibrate the analyte sensor, the current blood glucose measurement isused to determine an updated sensor sensitivity value which may be usedin conjunction with one or more prior sensitivity values or nominalsensitivity value.

Referring back to FIG. 6, when it is confirmed that the analyte sensoris in proper operation mode, the preprogrammed delivery rate executed bythe delivery unit 120 (FIG. 1) initiated when the sensor potentialfailure mode was detected, is terminated (630), and the closed loopcontrol operation based on the analyte sensor signals is re-initiated(640).

In the manner described above, in accordance with embodiments of thepresent disclosure, the operation of the closed loop control system 100may include monitoring the condition or parameters associated with theanalyte monitoring unit 130 and for example, the analyte sensor, andexecute one or more routines to instruct the delivery unit 120 totemporarily execute preprogrammed or modified delivery profiledetermined to be within the safety limits, or to disable the closed loopcontrol operation to maintain the desired degree of safety in using theclosed loop control system 100 (FIG. 1). Indeed, in one aspect, forexample, when an analyte sensor reading erroneously indicates a highlevel of glucose which is a false positive value and where the actualglucose level is lower than the measured high level of glucose, aspectsof the closed loop control operation are configured to establish a limitin the amount of insulin delivered so that when sensor failure isdetected, delivery of insulin amount beyond the determined safe level isprevented.

FIG. 7 is a flowchart illustrating variable rate control in a closedloop control system in accordance with one embodiment of the presentdisclosure. Referring to FIGS. 1 and 7, in one aspect, control unit 140executing the closed loop control algorithm in the closed loop controlsystem 100 receives monitored analyte level at a predetermined frequency(710). Based at least in part on the received monitored analyte level,the analyte variation level is determined (720). Thereafter, as shown,the medication delivery rate adjustment frequency is determined based onthe determined analyte variation level (730), and thereafter, thedelivery unit 120 (FIG. 1) is instructed to deliver the medication atthe determined medication delivery rate adjustment frequency (740). Thatis, in one aspect, the rate of monitored glucose level is associatedwith the adjustment of the frequency in which to instruct the deliveryunit 120 to deliver insulin.

For example, in one aspect, the control unit 140 may be configured tomonitor the glucose level from the analyte monitoring unit 130 at ahigher frequency (such as, for example once per minute), and also,adjust the rate of insulin delivery by the delivery unit 120 (FIG. 1) ata lower frequency (for example, once every 15 minutes). Indeed, it maybe unnecessary to adjust the rate of insulin delivery more frequentlythan once every 15 minutes when the monitored glucose level (at a higherfrequency) does not indicate significant variation in the glucose level.Accordingly, control unit 140 may be configured to issue an instructionor command to the delivery unit 120 once every 15 minutes (or some othersuitable interval) to vary the delivery rate based on the glucose level.

One advantage resulting from the less frequent delivery rate adjustmentis the conservation of power in the control unit 140 and/or the deliveryunit 120. That is, battery power may be conserved by avoiding thegeneration, communication and/or execution of instructions or commandsassociated with determining and implementing modification to the insulindelivery rate. On the other hand, since the glucose level is monitoredevery minute (or at a more frequent time interval), control unit 140 isconfigured to monitor the variation in the glucose level monitored, andas long as the variation is within a threshold level, the correspondinginsulin level delivery adjustment determination is not executed with thesame or similar frequency.

However, when the variation in the monitored glucose level exceeds thepredetermined threshold level indicating a large variation in themonitored glucose level, or in the cases where a meal event orcarbohydrate intake event occurs which will impact the monitored glucoselevel, it may be desirable to adjust the rate of insulin delivery to bemore frequent (for example, adjustment to the delivery rate once every 5minutes rather than 15 minutes, or with each determination of theglucose level). In this manner, to the extent that adjustment to theinsulin delivery rate is desirable, the frequency of the adjustment maybe associated with the monitored glucose level such that, for example,control unit 140 may be configured to determine, with each receivedglucose value, whether adjustment to the insulin delivery rate isneeded.

FIG. 8 is a flowchart illustrating variable rate control in a closedloop control system in accordance with another embodiment of the presentdisclosure. Referring to FIGS. 1 and 8, control unit 140 (FIG. 1) in oneaspect may be configured to instruct the delivery unit 120 (FIG. 1) todeliver medication based on closed loop control parameters at a firstdelivery rate adjustment frequency (810). Thereafter, the analytevariation level is determined based on the monitored analyte level at apredetermined frequency (820). Referring back to FIG. 8, one or morecondition information (for example, but not limited to an anticipatedmeal event) associated with the closed loop control parameters isreceived (830). Thereafter, a second delivery rate adjustment frequencyis determined based on the analyte level variation and/or receivedcondition information (840), and the medication delivery is executed(for example, by the insulin delivery unit 120 (FIG. 1)) at thedetermined second delivery rate adjustment frequency (850).

In this manner, in one aspect, control unit 140 is configured tomaximize responsiveness to substantial variation in monitored glucoselevel, or in anticipation of variation in glucose level, while providinglower power requirements for the various components of the system 100(FIG. 1). Within the scope of the present disclosure, other suitabletime intervals or frequency may be used for the glucose monitoring, andfurther, the associated adjustment to the insulin delivery rate.

That is, embodiments of the present disclosure allow for lower rate ofcontrol commands, for example, where the delivery unit 120 and theanalyte monitoring unit 130 are configured in the system 100 as separatecomponents, with the control unit 140 provided with the analytemonitoring unit 130 and communicating wirelessly with the delivery unit120, and each being powered by a respective power supply such as abattery.

FIGS. 9-10 are flowcharts illustrating blood glucose measurement toimprove accuracy of the closed loop control system in accordance withanother embodiment of the present disclosure. Referring to FIGS. 1, 9and 10, closed loop operation parameters are monitored (910) and whenonset of medication delivery level (for example, a large insulin dosagelevel) that exceeds a predetermined threshold level is detected (920) ablood glucose measurement information is received (930) (for example,from a blood glucose meter or manually entered by user input). Based onthe received blood glucose measurement information, it is determinedwhether the received blood glucose measurement is within a predeterminedmargin of error to a time corresponding analyte sensor data (940). Inother words, it is determined whether the sensor data correlates to theblood glucose measurement within a predetermined margin of error.

Referring back to FIG. 9, if it is determined that the analyte sensordata and the blood glucose measurement are within the predeterminedmargin of error, then the detected onset of medication delivery level ismaintained and the delivery unit 120 delivers that level of medication(950). On the other hand, if it is determined that the blood glucosemeasurement received is not within the predetermined margin of error(940), then referring back to FIG. 10 (960), the closed loop controlparameters associated with the analyte monitoring and/or the medicationdelivery are retrieved (1010), and the retrieved closed loop controlparameters are evaluated based on the received blood glucose measurement(1020).

For example, one or more of the closed loop control parameters retrievedmay include a request for an additional blood glucose measurement value,an instruction to modify or adjust insulin delivery rate, command todisable closed loop control operation and initiate semi-closed loopcontrol operation or manual control operation, or instruction torecalibrate the analyte sensor, among others. Referring back to FIG. 10,upon evaluation of the retrieved one or more closed loop controlparameters, the retrieved one or more parameters may be modified (1030)and thereafter the modified one or more closed loop control parametersis stored (1040).

In this manner, for example, under the control of the control unit 140(FIG. 1) executing the closed loop control algorithm, when it isdetected that a large amount of insulin is to be delivered by thedelivery unit 120, the control unit 140, as a safety measure, forexample, may prompt the user to enter a current blood glucosemeasurement (for example, using an in vitro blood glucose meter), toconfirm and/or verify the accuracy of the analyte sensor level from theanalyte monitoring unit 130 based on which the large amount of insulinto be delivered was determined for execution. For example, a Kalmanfilter may be used as part of the control unit 140 to process theanalyte sensor data and the received blood glucose measurement tooptimally adjust the insulin level.

In one aspect, the request or prompt to enter the blood glucosemeasurement may be initiated when the determined insulin amount fordelivery in the closed loop control system 100 exceeds a predeterminedsafety level established, for example, by a healthcare provider orphysician, where the safety level includes, for example, the highestinsulin delivery rate without blood glucose measurement confirmation.Within the scope of the present disclosure, other conditions orparameters may be used to trigger the request for blood glucosemeasurement for confirming sensor accuracy, glucose level verification,and the like.

Further, in another aspect, the control unit 140 may be configured todiscontinue requesting blood glucose measurements (even when the insulinlevel to be delivered exceeds the predetermined safety level) when apredetermined number of successful blood glucose measurementconfirmations have occurred and the analyte sensor is consideredaccurate and stable. Still another aspect of the present disclosureincludes modifying the safety level for the highest rate of insulindelivery based on the determination of sensor stability and accuracy inview of, for example, successive confirmation of blood glucosemeasurements to the corresponding sensor values.

FIG. 11 is a flowchart illustrating medication delivery information todetermine analyte sensor condition in a closed loop control system inaccordance with one embodiment of the present disclosure. Referring toFIGS. 1 and 11, in the closed loop control operation state of the closedloop control system 100, control unit 140 (FIG. 1) in one aspectmonitors closed loop operation parameters (1110) and performs apredictive modeling analysis of the monitored closed loop controloperation parameters associated with the medication delivery and analytesensor to determine a predictive glucose response (1120). Thereafter,the determined predictive glucose response is compared with thecorresponding monitored analyte sensor signal (1130) and a sensor signalcondition based on the comparison is determined (1140). For example,based on the comparison, the sensor signal condition may indicate asignal attenuation condition of the glucose sensor. Referring back toFIG. 11, when the sensor signal condition indicates an adverse signalcondition or a condition associated with a corrective action orprocedure, the corresponding corrective procedure is retrieved andexecuted by the control unit 140 (1150).

In this manner, in one aspect, using the insulin delivery information,and based on a predictive model implemented to determine a modeledglucose sensor signal, the robustness of the closed loop control system100 may be enhanced and accuracy of the overall system 100 improved. Inone aspect, the predictive model used may include a routine or algorithmthat describes glucose response or behavior based on one or moreexogenous factors including, among others, insulin delivery information,meal intake, exercise events, and the like, as well as prior monitoredsensor data. Accordingly, in one aspect, real time insulin deliveryinformation may be used to improve glucose sensor anomalies such assignal dropouts and early signal attenuation.

For example, as discussed above, the generated modeled glucose sensorresponse is compared in one aspect to the actual measured sensor data,and based on the comparison, it may be determined that anomalies existwith the glucose sensor. For example, control unit 140 may determine,based on the comparison that sensor signal dropout or early signalattenuation is detected, and thus may prompt the user to enter areference blood glucose measurement value. In addition, certain alarm ornotification functions related to the monitored analyte level such ashypoglycemic alarm, output display of glucose values in real time, maybe modified or disabled given the detected anomaly with the sensorsignal.

In one aspect, other variables may be compared based on the predictivemodel and the actual measured sensor signal such as, for example, rateof change of the glucose level determined based on the actual measuredvalues from the sensor and compared with the modeled rate of changeinformation. Additionally, upon determination of the sensor signal dropout or early signal attenuation condition, operations of the analytemonitoring unit 130 may be adjusted accordingly, for example, tomitigate or address the signal abnormality. For example, when suchsensor signal condition indicates adverse signal condition at the timeof scheduled sensor calibration, the calibration attempt may bedisqualified and the user may be instructed to perform anothercalibration or to delay the calibration until the sensor signal hasstabilized and the indicated adverse signal condition is no longerpresent.

FIG. 12 is a flowchart illustrating detection of false hypoglycemicalarm condition in a closed loop control system in accordance with oneembodiment of the present disclosure. Referring to FIGS. 1 and 12, inone aspect, condition associated with hypoglycemic state is detected(1220) based on monitored closed loop operation parameters (1210) by,for example, the control unit 140 (FIG. 1). Upon detection of thecondition associated with the hypoglycemic state, a pre-hypoglycemiccondition notification routine is performed (1230). If the hypoglycemicstate or condition is confirmed (1240), then a correspondingnotification such as a hypoglycemic alarm is output (1250), and theclosed loop control parameters are accordingly updated to take intoaccount of the detected hypoglycemic condition (1260).

On the other hand, if the hypoglycemic condition is not confirmed(1240), then the routine returns to monitor the closed loop operationparameters (1210). That is, in one aspect, when a condition associatedwith hypoglycemia is detected, the control unit 140 may be configured toconfirm the presence of the detected hypoglycemic state before assertingan alarm notification, for example, to the user. In this manner,potential false hypoglycemic alarms are minimized based on, for example,presence of glucose sensor signal dropout or early signal attenuation orother sensor anomaly state that indicates a false low glucose level.

For example, in accordance with the embodiments of the presentdisclosure, hypoglycemic alarms or notifications are provided withsensor signal dropout tolerance levels. More specifically, based on themedication delivery rate information, and other parameters associatedwith the closed loop control operation, the control unit 140 may beconfigured to determine a degree or level of uncertainly in the measuredsensor signal based on the predicted or anticipated glucose levelderived, for example, based on the parameters associated with the closedloop control algorithm, including, such as amount of insulin delivered,insulin on board information, glucose rate of change information, amongothers.

In one aspect, when the onset of a potential hypoglycemic condition isdetected, the control unit 140 may be configured to confirm the presenceof the hypoglycemic condition, by for example, requiring additionalsensor data to be received and analyzed and determining that the sensorsignals indicate a persistent low glucose value. In this manner, ratherthan asserting the hypoglycemic condition notification immediately upondetection of a sensor signal level below the alarm threshold, controlunit 140 in one aspect is configured to confirm the presence of thehypoglycemic condition, and upon confirmation, to assert the alarm ornotification associated with the hypoglycemic condition.

In another aspect, upon detection of a potential hypoglycemic condition,control unit 140 may be configured to initiate and execute a sensorsignal dropout detection algorithm to determine whether the detectedpotential hypoglycemic condition is associated with sensor signaldropout or attributable to low glucose level. Moreover, in a furtheraspect, upon detection of the potential hypoglycemic condition, controlunit 140 may be configured to assert an alert notification (associatedwith less urgency or criticality), and if the potential hypoglycemiccondition is confirmed, to assert the hypoglycemic condition alarm. Forexample, the alert notification may include a single audible beep thatdoes not repeat. If the glucose is persistently below the hypoglycemicthreshold (or alarm condition level), or below a lower safety threshold,the notification may be escalated to an alarm, for example, with threeconsecutive audible beeps with or without repeat routines. In thismanner, for example, if the sensor signal dropout occurs duringnighttime when the user is asleep, the alert notification may not beloud enough to wake the user, but may be sufficient to cause the user tomove or roll over in bed, for example, resulting in the sensor dropoutcondition being no longer present.

In the manner described, in accordance with the various embodiments ofthe present disclosure, a robust closed loop control system is providedthat includes safety checks and verifications to address potentialerrors and/or anomalies in detected or monitored conditions and/orparameters enhancing the accuracy and confidence level of the closedloop control operation in the treatment of diabetic conditions.

A method in accordance with one embodiment includes monitoring controlparameters in a closed loop control operation including continuouslymonitoring glucose level and automatic administration of a medication,detecting a condition associated with hypoglycemia, determining aprobability of the detected condition associated with hypoglycemiaexceeding a threshold level, and outputting a notification based uponthe determination.

The method may include updating the closed loop control operation tomodify the administration of the medication.

In one aspect, the medication may include insulin or glucagon or acombination thereof.

Also, determining the probability of the detected condition may includeretrieving the monitored glucose level over a predetermined time period,and determining whether the signal level associated with the glucoselevel monitored indicates a persistent hypoglycemic condition.

Additionally, outputting the notification may include outputting analert notification upon detection of the condition associated withhypoglycemia, and outputting an alarm notification when the determinedprobability of the detected condition exceeds the threshold level, wherethe alarm notification may be more intense than the alert notification.

Also, in another aspect, the alert notification or the alarmnotification may include one or more of a visual notification, anaudible notification, a vibratory notification, or one or morecombinations thereof.

When the determined probability exceeds the threshold level, in oneaspect, the hypoglycemic condition is confirmed.

The method may also include adjusting the rate of medicationadministration.

The detected condition associated with hypoglycemia in another aspectmay be derived from an analyte sensor signal.

A device in accordance with another embodiment includes one or moreprocessors, and a memory operatively coupled to the one or moreprocessors, the memory for storing instructions which, when executed bythe one or more processors, cause the one or more processors to monitorcontrol parameters in a closed loop control operation includingcontinuously monitoring glucose level and automatic administration of amedication, detect a condition associated with hypoglycemia, determine aprobability of the detected condition associated with hypoglycemiaexceeding a threshold level, and output a notification based upon thedetermination.

The memory for storing instructions which, when executed by the one ormore processors, may cause the one or more processors to update theclosed loop control operation to modify the administration of themedication.

The medication may include insulin or glucagon or a combination thereof.

The memory for storing instructions which, when executed by the one ormore processors, may cause the one or more processors to retrieve themonitored glucose level over a predetermined time period, and determinewhether the signal level associated with the glucose level monitoredindicates a persistent hypoglycemic condition.

The memory for storing instructions which, when executed by the one ormore processors, may cause the one or more processors to output an alertnotification upon detection of the condition associated withhypoglycemia, and output an alarm notification when the determinedprobability of the detected condition exceeds the threshold level.

The alarm notification may be more intense than the alert notification.

The alert notification or the alarm notification may include one or moreof a visual notification, an audible notification, a vibratorynotification, or one or more combinations thereof.

When the determined probability exceeds the threshold level, in anotheraspect, the hypoglycemic condition is confirmed.

The memory for storing instructions which, when executed by the one ormore processors, may cause the one or more processors to adjust the rateof medication administration.

In another aspect, the detected condition associated with hypoglycemiamay be derived from an analyte sensor signal.

What is claimed is:
 1. A method comprising: determining a predictiveglucose response based on prior monitored glucose sensor data and one ormore exogenous factors; detecting a condition associated withhypoglycemia including determining a level of uncertainty in a monitoredglucose level based on a predicted or anticipated glucose level;determining a probability that the detected condition associated withhypoglycemia corresponds to a hypoglycemic condition includingdetermining whether glucose sensor data indicates a persistent lowglucose level; comparing the determined probability that the detectedcondition associated with hypoglycemia corresponds to the hypoglycemiccondition, to a probability threshold level to confirm a presence of thehypoglycemic condition; modifying a first medication delivery rateadjustment frequency to a second medication delivery rate adjustmentfrequency based on a variation in the monitored glucose level; anddetermining periodically at the second medication delivery rateadjustment frequency whether to adjust a medication delivery rate. 2.The method of claim 1, further including outputting a notification whenthe determined probability exceeds the probability threshold level andafter the presence of the hypoglycemic condition is confirmed, whereinoutputting the notification reduces outputting false low glucose alarmsbased on a presence of a glucose sensor signal dropout or a glucosesensor early signal attenuation condition.
 3. The method of claim 1,wherein when the determined probability exceeds the probabilitythreshold level, the hypoglycemic condition is confirmed.
 4. The methodof claim 1, further comprising reverting to a pre-programmed medicationdelivery rate when the determined probability exceeds the probabilitythreshold level, wherein the pre-programmed medication delivery rate isless than a delivery rate of an administration of a medication of aclosed loop control operation.
 5. The method of claim 1, furthercomprising delaying outputting a notification for a predetermined periodof time when the determined probability exceeds the probabilitythreshold level and after the presence of the hypoglycemic condition isconfirmed.
 6. The method of claim 5, wherein the predetermined period oftime is based, at least in part, on a time required to determine whetherthe probability of the detected condition associated with hypoglycemiaexceeds the probability threshold level.
 7. The method of claim 1,wherein determining the level of uncertainty in the monitored glucoselevel includes determining a confidence level of an accuracy of themonitored glucose level, wherein the confidence level is based, at leastin part, on at least one of an amount of insulin delivered, insulin onboard information, and rate of change information.
 8. The method ofclaim 1, further comprising: determining whether detected glucose sensoranomalies exceed a preset safety level; and when the detected glucosesensor anomalies exceed the preset safety level, administering amedication according to a pre-programmed delivery rate that is withinthe preset safety level.
 9. The method of claim 8, further comprisingdisabling a closed loop control operation when a presence of thedetected glucose sensor anomalies is not confirmed within apredetermined time period.
 10. The method of claim 1, wherein theglucose level is monitored using a glucose sensor including a pluralityof electrodes including a working electrode, wherein the workingelectrode comprises a glucose-responsive enzyme and a mediator, whereinat least one of the glucose-responsive enzyme and the mediator ischemically bonded to a polymer disposed on the working electrode, andwherein at least one of the glucose-responsive enzyme and the mediatoris crosslinked with the polymer.